阅读说明：本技术 一种双酰胺类化合物及其制备方法与应用 (Bisamide compound and preparation method and application thereof ) 是由 张建军 许庆博 沈生强 金淑惠 于 2019-09-09 设计创作，主要内容包括：本发明涉及一种双酰胺类化合物及其制备方法与应用,它的结构式式(I)或式(II)所示化合物,式(I)记为CAUZX-A,式(II)记为CAUZX-B,或其在药学上可接受的盐；式(I)中R<Sub>1</Sub>为三氟甲基、正丙基、异丙基、正丁基、苯基、邻氟苯基、间氟苯基、对氟苯基、间甲基苯基、对甲基苯基、对甲氧基苯基、邻溴苯基、对溴苯基、邻三氟甲基苯基、间三氟甲基苯基、对硝基苯基、间氯苯基、对氯苯基、对苯基苯基、2,4-二氯-苯基、对甲氧基苯乙基、4-氯-3-三氟甲基苯基、2-呋喃、2-吡啶、4-吡啶；式(II)中R<Sub>2</Sub>为甲基,苯基,对甲基苯基。本发明所述化合物具有很高的农药研究价值。(The invention relates to a bisamide compound and a preparation method and application thereof, and the bisamide compound has a structural formula (I) or a compound shown in a formula (II), wherein the formula (I) is CAUZX-A, the formula (II) is CAUZX-B, or pharmaceutically acceptable salts thereof; r in the formula (I) 1 Is trifluoromethyl, n-propyl, isopropyl, n-butyl, phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, p-methoxyphenyl, o-bromophenyl, p-bromophenyl, o-trifluoromethylbenzenePhenyl, m-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, p-phenylphenyl, 2, 4-dichloro-phenyl, p-methoxyphenethyl, 4-chloro-3-trifluoromethylphenyl, 2-furan, 2-pyridine, 4-pyridine; r in the formula (II) 2 Is methyl, phenyl, p-methylphenyl. The compound has high pesticide research value.)

1. A bisamide compound is a compound shown as a formula (I) or a formula (II), or a pharmaceutically acceptable salt thereof;

r in the formula (I)₁Is trifluoromethyl, n-propyl, isopropyl, n-butyl, phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, p-methoxyphenyl, o-bromophenyl, p-bromophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, p-phenylphenyl, 2, 4-dichloro-phenyl, p-methoxyphenylethyl, 4-chloro-3-trifluoromethylphenyl, 2-furan, 2-pyridine, or a mixture thereof,One of 4-pyridine;

r in the formula (II)₂Is one of methyl, phenyl and p-methylphenyl.

2. The process for producing the bisamide-based compound according to claim 1, wherein the process for producing the compound represented by the formula (I) comprises the steps of:

in an anhydrous solvent, carrying out a condensation reaction on a compound shown as a formula (VIII) and a compound shown as a formula VIIII under an alkaline condition to obtain a compound shown as a formula (I), wherein a reagent used under the alkaline condition is 4-dimethylaminopyridine, the using amount of the 4-dimethylaminopyridine is 3% of that of the compound shown as the formula (VIII) in terms of molar ratio, the PH under the alkaline condition is 8-9, a condensation agent is added in the condensation reaction, the condensation agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide, and the molar ratio of the compound shown as the formula (VIII) to the condensation agent is 1: 1.01-10, wherein the temperature of the condensation reaction is room temperature, the time of the condensation reaction is 4-12 h, and the anhydrous solvent is anhydrous dichloromethane;

a process for the preparation of a compound of formula (II) comprising the steps of:

in an anhydrous solvent, carrying out a condensation reaction on a compound shown as a formula (VIII) and a compound shown as a formula X to obtain a compound shown as a formula (II), adding an alkaline reagent into the condensation reaction, wherein the alkaline reagent is triethylamine, the dosage of the triethylamine is 1.5-2 times of that of the compound shown as the formula (VIII) in terms of molar ratio, the temperature of the condensation reaction is 0 ℃, the time of the condensation reaction is 2-3 h, and the anhydrous solvent is anhydrous dichloromethane;

a process for preparing a compound of formula (VIII) comprising the steps of:

1) reacting a compound shown in a formula (III) with a reagent ethyl cyanoacetate in a solvent under an alkaline condition to obtain a compound shown in a formula (IV); the molar ratio of the compound shown in the formula (III) to ethyl cyanoacetate is 1: 1.01-10, adding an inorganic base in the step 1), wherein the molar ratio of the compound shown in the formula (III) to the inorganic base is 1: 1.5-10, wherein the inorganic base is anhydrous potassium carbonate or anhydrous sodium carbonate; the reaction temperature is 60-70 ℃, the reaction time is 4-8 h, and the solvent is dimethyl sulfoxide;

2) decarboxylating the compound shown in the formula (IV) in a solvent under an acidic condition to obtain a compound shown in the formula (V); in the step 2), inorganic acid is adopted to adjust the pH value to be less than or equal to 2, and the inorganic acid is hydrochloric acid or sulfuric acid; the reaction temperature is 120-130 ℃, the reaction time is 4-8 h, and the solvent is N, N-dimethylformamide;

3) in a solvent, a compound shown as a formula (V) is catalyzed by Pd/C to obtain a compound shown as a formula (VI); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (V); the reaction temperature is room temperature, the reaction time is 4-7 h, and the solvent is methanol;

4) carrying out condensation reaction on the compound shown in the formula (VI) and a reagent o-nitrobenzoic acid to obtain a compound shown in a formula (VII); the mol ratio of the compound shown in the formula (VI) to the o-nitrobenzoic acid is 1: 1.01-10, adding a condensing agent in the condensation reaction, wherein the molar ratio of the compound shown as the formula (VI) to the condensing agent is 1: 1.01 to 10, wherein the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide, and the organic base is added in the step 4), the organic base is 4-dimethylaminopyridine, and the amount of the organic base is 3% of that of the compound shown in the formula (VI) in terms of molar ratio; the reaction time is 5-12 h, and the reaction temperature is room temperature;

5) in a solvent, a compound shown as a formula (VII) is subjected to Pd/C catalysis to obtain a compound shown as a formula (VIII); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (VII); the reaction temperature is room temperature, the reaction time is 1-3 h, and the solvent is methanol.

3. A bactericide, the active ingredient of which is a compound shown as a formula (I) or a formula (II) or a pharmaceutically acceptable salt thereof.

4. The bactericidal agent of claim 3, wherein the bactericidal agent is in a pharmaceutically acceptable dosage form; the formulation comprises at least one of missible oil, suspending agent, powder, aqueous agent, smoke agent, granules and seed coating agent.

5. A nematicide, the active ingredient of which is a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof.

6. The nematicide of claim 5, wherein the nematicide is in a pharmaceutically acceptable dosage form; the preparation formulation comprises at least one of wettable powder, soluble powder, water dispersible granules, missible oil, suspending agents, powder, aqueous agents, smoke agents, granules and seed coating agents.

7. The bactericide or nematicide emulsifiable concentrate is characterized by comprising the following substances in percentage by mass: 1-10% of the bisamide compound or the pharmaceutically acceptable salt thereof according to claim 1, 5-15% of an emulsifier, 0.1-1% of a penetrating agent, and the balance of a solvent; the emulsifier is a surfactant, and the surfactant comprises at least one of Nongru 0203B, Nongru 0208, Nongru GFC, OP-10 and Tween-60; the penetrant comprises at least one of JFC-2, TX-10, FP-T, OX-408, OX-406, N-2 and UC-12A; the solvent is toluene and/or xylene.

8. The wettable pesticide powder is characterized by comprising the following substances in parts by mass: 15-50 parts of bisamide compound or pharmaceutically acceptable salt thereof according to claim 1, 10-20 parts of surfactant and 30-75 parts of white carbon black; the surfactant comprises at least one of SP-408, APG-810, TA-15, AOS, NNO, MF, AEC, M4600, SP-2728, and VESTVACO.

9. Use of the bisamide compound according to claim 1 or a pharmaceutically acceptable salt thereof for nematicidal or nematicidal agents.

10. Use of the bisamide compound or a pharmaceutically acceptable salt thereof according to claim 1 for sterilization or preparation of a bactericide.

Technical Field

The invention relates to the technical field of organic compound synthesis, in particular to a bisamide compound, a preparation method thereof and application of the bisamide compound as a nematicide and a bactericide.

Background

Amide compounds are widely concerned chemical structures in the research fields of medicines, pesticides, veterinary drugs and the like, and often have unique activities of killing insects, killing mites, killing bacteria, weeding, regulating plant growth and the like. The amide compounds have the history of about 50 years and occupy a large proportion in the bactericide, and varieties with novel structures are reported all the time, the amide compounds are full of the bactericide, the amide compounds account for about one fourth of the total number of the existing bactericidal active pesticide compounds, the Bayer company obtains the bactericide fluopyram (fluopicolide) on the basis of the derivation of 2, 3-dichloro-5-trifluoromethylpyridine, and further optimizes the bactericide to obtain the fluopyram, and the fluopyram has bactericidal and nematicidal activities.

Due to the development of pesticide resistance, new pesticides with independent intellectual property rights are required to be developed to guarantee the food safety of China, the inventor develops molecular design and activity research of novel amide compounds according to the splicing principle of active substructures, deeply explores the influence of molecules which are different from the protective amide structures of the existing patents and contain characteristic bisamide structures on the pesticide activity, and further guides the research of high-activity novel pesticide candidate compounds. A series of compounds containing bisamide structures with brand-new structures are designed and synthesized, and the compounds are subjected to extensive bactericidal activity determination and structure-activity relationship research to find out good structures of the bactericidal and nematicidal active compounds.

Disclosure of Invention

In view of the defects in the prior art, the invention aims to provide a bisamide compound or a pharmaceutically acceptable salt thereof.

In order to achieve the above purposes, the technical scheme adopted by the invention is as follows:

a bisamide compound is a compound shown as a formula (I) or a formula (II), wherein the formula (I) is recorded as CAUZX-A, the formula (II) is recorded as CAUZX-B, or a pharmaceutically acceptable salt thereof;

r in the formula (I)₁Is one of trifluoromethyl, n-propyl, isopropyl, n-butyl, phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, p-methoxyphenyl, o-bromophenyl, p-bromophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, p-phenylphenyl, 2, 4-dichloro-phenyl, p-methoxyphenethyl, 4-chloro-3-trifluoromethylphenyl, 2-furan, 2-pyridine and 4-pyridine;

r in the formula (II)₂Is one of methyl, phenyl and p-methylphenyl.

A preparation method of a compound CAUZX-A shown as a formula (I) comprises the following steps:

1) reacting a compound shown in a formula (III) with a reagent ethyl cyanoacetate in a solvent under an alkaline condition to obtain a compound shown in a formula (IV); the molar ratio of the compound shown in the formula (III) to ethyl cyanoacetate is 1: 1.01-10, adding an inorganic base in the step 1), wherein the molar ratio of the compound shown in the formula (III) to the inorganic base is 1: 1.5-10, wherein the inorganic base is anhydrous potassium carbonate or anhydrous sodium carbonate; the reaction temperature is 60-70 ℃, the reaction time is 4-8 h, and the solvent is dimethyl sulfoxide;

2) decarboxylating the compound shown in the formula (IV) in a solvent under an acidic condition to obtain a compound shown in the formula (V); in the step 2), inorganic acid is adopted to adjust the pH value to be less than or equal to 2, and the inorganic acid is hydrochloric acid or sulfuric acid; the reaction temperature is 120-130 ℃, the reaction time is 4-8 h, and the solvent is N, N-Dimethylformamide (DMF);

3) in a solvent, a compound shown as a formula (V) is catalyzed by Pd/C to obtain a compound shown as a formula (VI); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (V); the reaction temperature is room temperature, specifically 25 ℃, the reaction time is 4-7 h, and the solvent is methanol;

4) carrying out condensation reaction on the compound shown in the formula (VI) and a reagent o-nitrobenzoic acid to obtain a compound shown in a formula (VII); the mol ratio of the compound shown in the formula (VI) to the o-nitrobenzoic acid is 1: 1.01-10, adding a condensing agent in the condensation reaction, wherein the molar ratio of the compound shown as the formula (VI) to the condensing agent is 1: 1.01-10, wherein the condensing agent is EDCI or Dicyclohexylcarbodiimide (DCC), organic base is added in the step 4), the organic base is DMAP, and the amount of the organic base is 3% of that of the compound shown in the formula (VI) in terms of molar ratio; the reaction time is 5-12 h, and the reaction temperature is room temperature;

5) in a solvent, a compound shown as a formula (VII) is subjected to Pd/C catalysis to obtain a compound shown as a formula (VIII); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (VII); the reaction temperature is room temperature, specifically 25 ℃, the reaction time is 1-3 h, and the solvent is methanol;

6) in an anhydrous solvent, carrying out a condensation reaction on a compound shown as a formula (VIII) and a compound shown as a formula VIIII under an alkaline condition to obtain a compound shown as a formula (I), wherein a reagent used under the alkaline condition is 4-Dimethylaminopyridine (DMAP), the using amount of the DMAP is 3% of that of the compound shown as the formula (VIII), the PH under the alkaline condition is 8-9, a condensing agent is added in the condensation reaction, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI) or DCC, and the molar ratio of the compound shown as the formula (VIII) to the condensing agent is 1: 1.01-10, the temperature of the condensation reaction is room temperature, specifically 25 ℃, the time of the condensation reaction is 4-12 hours, specifically 12 hours, 4-12 hours and 7-12 hours, the anhydrous solvent is anhydrous dichloromethane, and the preparation method further comprises the steps of extraction, drying and column chromatography.

A preparation method of a compound CAUZX-B shown as a formula (II) comprises the following steps:

1) reacting a compound shown in a formula (III) with a reagent ethyl cyanoacetate in a solvent under an alkaline condition to obtain a compound shown in a formula (IV); the molar ratio of the compound shown in the formula (III) to ethyl cyanoacetate is 1: 1.01-10, adding an inorganic base in the step 1), wherein the molar ratio of the compound shown in the formula (III) to the inorganic base is 1: 1.5-10, wherein the inorganic base is anhydrous potassium carbonate or anhydrous sodium carbonate; the reaction temperature is 60-70 ℃, the reaction time is 4-8 h, and the solvent is dimethyl sulfoxide;

2) decarboxylating the compound shown in the formula (IV) in a solvent under an acidic condition to obtain a compound shown in the formula (V); in the step 2), inorganic acid is adopted to adjust the pH value to be less than or equal to 2, and the inorganic acid is hydrochloric acid or sulfuric acid; the reaction temperature is 120-130 ℃, the reaction time is 4-8 h, and the solvent is DMF;

3) in a solvent, a compound shown as a formula (V) is catalyzed by Pd/C to obtain a compound shown as a formula (VI); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (V); the reaction temperature is room temperature, specifically 25 ℃, the reaction time is 4-7 h, and the solvent is methanol;

4) carrying out condensation reaction on the compound shown in the formula (VI) and a reagent o-nitrobenzoic acid to obtain a compound shown in a formula (VII); the mol ratio of the compound shown in the formula (VI) to the o-nitrobenzoic acid is 1: 1.01-10, adding a condensing agent in the condensation reaction, wherein the molar ratio of the compound shown as the formula (VI) to the condensing agent is 1: 1.01-10, the condensing agent is EDCI or DCC, organic base is added in the step 4), the organic base is DMAP, and the amount of the organic base is 3% of that of the compound shown in the formula (VI) in terms of molar ratio; the reaction time is 5-12 h, and the reaction temperature is room temperature;

5) in a solvent, a compound shown as a formula (VII) is subjected to Pd/C catalysis to obtain a compound shown as a formula (VIII); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (VII); the reaction temperature is room temperature, specifically 25 ℃, the reaction time is 1-3 h, and the solvent is methanol;

6) in an anhydrous solvent, carrying out a condensation reaction on a compound shown in a formula (VIII) and a compound shown in a formula X to obtain a compound shown in a formula (II), adding an alkaline reagent into the condensation reaction, wherein the alkaline reagent is triethylamine, the dosage of the triethylamine is 1.5-2 times of that of the compound shown in the formula (VIII) in terms of molar ratio, the temperature of the condensation reaction is 0 ℃, the time of the condensation reaction is 2-3 h, specifically 2h or 3h, and the anhydrous solvent is anhydrous dichloromethane.

In the invention, the room temperature is 10-30 ℃.

A bactericide, the active ingredient of which is a compound shown as a formula (I) or a formula (II) or a pharmaceutically acceptable salt thereof.

On the basis of the scheme, the bactericide is a pharmaceutically acceptable dosage form; the formulation comprises at least one of missible oil, suspending agent, powder, aqueous agent, smoke agent, granules and seed coating agent.

A nematicide, the active ingredient of which is a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof.

On the basis of the scheme, the nematicide is a pharmaceutically acceptable dosage form; the preparation formulation comprises at least one of wettable powder, soluble powder, water dispersible granules, missible oil, suspending agents, powder, aqueous agents, smoke agents, granules and seed coating agents.

A bactericide or nematicide emulsifiable concentrate comprises the following substances in percentage by mass: 1-10% of the bisamide compound or pharmaceutically acceptable salt thereof, 5-15% of an emulsifier, 0.1-1% of a penetrating agent and the balance of a solvent;

the emulsifier is a surfactant, and the surfactant comprises at least one of Nongru 0203B, Nongru 0208, Nongru GFC, OP-10 and Tween-60;

the penetrant comprises at least one of JFC-2, TX-10, FP-T, OX-408, OX-406, N-2 and UC-12A;

the solvent is toluene and/or xylene.

The wettable pesticide powder comprises the following substances in parts by mass: 15-50 parts of the bisamide compound or pharmaceutically acceptable salt thereof, 10-20 parts of a surfactant and 30-75 parts of white carbon black;

the surfactant comprises at least one of SP-408, APG-810, TA-15, AOS, NNO, MF, AEC, M4600, SP-2728, and VESTVACO.

The invention also provides the application of the bisamide compound or the pharmaceutically acceptable salt thereof in killing nematodes or preparing nematicides.

The invention also provides application of the bisamide compound or the pharmaceutically acceptable salt thereof in sterilization or preparation of a bactericide.

The invention has the beneficial effects that: the invention takes fluopyram with bactericidal activity and nematocidal activity as a lead compound to synthesize a series of novel bisamide compounds, the raw materials for preparing the compound CAUZX are cheap, the reaction route is simple, and the product has good activity. Most of the CAUZX compounds show excellent bactericidal and nematicidal activities, wherein the bactericidal activity and nematicidal activity of CAUZX-A-11 on apple canker, sclerotinia sclerotiorum and rhizoctonia solani exceed those of a lead compound, namely fluopyram. The compound has high pesticide research value.

Drawings

The invention has the following drawings:

FIG. 1 is the NMR spectrum of compound CAUZX-A-01.

FIG. 2 is the NMR carbon spectrum of the compound CAUZX-A-01.

FIG. 3 is the NMR spectrum of the compound CAUZX-B-01.

FIG. 4 is the NMR carbon spectrum of the compound CAUZX-B-01.

Detailed Description

The invention is described in further detail below with reference to figures 1-4.

The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.